Liver inflammation and steatosis are fundamental pathological changes that contribute to the development of systemic insulin resistance in obesity. However, the molecular and cellular events that initiate and propagate obesity-related non-alcoholic fatty liver disease (NAFLD) remain unclear. We reported that neutrophil elastase (NE) knockout (KO) mice are resistant to a high-fat diet (HFD)-induced systemic inflammation, fatty liver, and insulin resistance. HFD feeding of WT mice for only a few days increases proinflammatory neutrophil production preceding vascular leakage, leukocyte infiltration and steatosis in the liver. Based on our preliminary data, we hypothesize that inhibition of NE prevents HFD-induced proinflammatory neutrophil production via altering NAD-dependent deacetylase Sirtuin 1 (Sirt1) signaling pathway in neutrophils. Inhibition of NE also increases the levels of high-molecular-weight adiponectin that activates AMP-kinase (AMPK) and fatty acid oxidation, thus attenuating HFD-induced steatosis in the liver. In addition, inhibition of NE also ameliorated high-fat high-carb diet (HFHCD)- induced steatosis, nonalcoholic steatohepatitis (NASH) and collagen deposition in the liver. In this proposal, we will evaluate if Sirt1 in neutrophils and the adiponectin ? AMPK pathway in the liver are required for the beneficial effects of NE inhibition on diet-induced neutrophil phenotypic changes, inflammatory liver damage and steatosis. Successful completion of this project will shed new light on molecular and cellular mechanisms by which inhibition of NE prevent obesity-related NAFLD and insulin resistance.